The present invention relates to agents that act to antagonize the action of the glucagon peptide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.
Glucagon is a key hormonal agent that, in co-operation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells. Diabetes mellitus is a common disorder of glucose metabolism. The disease is characterized by hyperglycemia and may be classified as Type 1 diabetes, the insulin-dependent form, or Type 2 diabetes, which is non-insulin-dependent in character. Subjects with Type 1 diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with Type 1 or Type 2 diabetes, absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state. Both in healthy control animals as well as in animal models of Type 1 and Type 2 diabetes, removal of circulating glucagon with selective and specific antibodies has resulted in reduction of the glycemic level (Brand et al., Diabetologia 37, 985 (1994); Diabetes 43, [suppl 1], 172A (1994); Am. J. Physiol. 269, E469-E477 (1995); Diabetes 44 [suppl 1], 134A (1995); Diabetes 45, 1076 (1996)). These studies suggest that glucagon suppression or an action that antagonizes glucagon could be a useful adjunct to conventional antihyperglycemia treatment of diabetes. The action of glucagon can be suppressed by providing an antagonist or an inverse agonist, ie substances that inhibit or prevent glucagon-induced responses. The antagonist can be peptidic or non-peptidic in nature.
Native glucagon is a 29 amino acid peptide having the sequence:
Hisxe2x80x94Ser-Glu-Gly-Thr-Phe-Thrxe2x80x94Ser-Asp-Tyrxe2x80x94Ser-Lys-Tyr-Leu-Aspxe2x80x94Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH2. 
Glucagon exerts its action by binding to and activating its receptor, which is part of the Glucagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family (Jelinek et al., Science 259, 1614, (1993)). The receptor functions by activating the adenylyl cyclase second messenger system and the result is an increase in cAMP levels.
Several publications disclose peptides that are stated to act as glucagon antagonists. Probably, the most thoroughly characterized antagonist is DesHis1[Glu9]-glucagon amide (Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl. Acad. Sci. USA 90, 1662 (1993)). Other antagonists are DesHis1, Phe6[Glu9]-glucagon amide (Azizh et al., Bioorganic and Medicinal Chem. Lett. 16, 1849 (1995)) and NLeu9,Ala11,16-glucagon amide (Unson et al., J. Biol. Chem. 269 (17), 12548 (1994)).
Peptide antagonists of peptide hormones are often quite potent. However, they are generally known not to be orally available because of degradation by physiological enzymes, and poor distribution in vivo. Therefore, orally available non-peptide antagonists of peptide hormones are generally preferred. Among the non-peptide glucagon antagonists, a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethylamino]-6,7-dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J. L. et al., Bioorganic and Medicinal Chemistry Letters 2(9):915-918 (1992)). WO 94/14426 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists. U.S. Pat. No. 4,359,474 discloses the glucagon antagonistic properties of 1-phenyl pyrazole derivatives. U.S. Pat. No. 4,374,130 discloses substituted disilacyclohexanes as glucagon antagonists. WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as glucagon antagonists. U.S. Pat. No. 5,776,954 (Merck and Co., Inc.) discloses substituted pyridyl pyrroles as glucagon antagonists and WO 98/21957, WO 98/22108, WO 98/22109 and U.S. Pat. No. 5,880,139 (Merck and Co., Inc.) disclose 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. Furthermore, WO 97/16442 and U.S. Pat. No. 5,837,719 (Merck and Co., Inc.) disclose 2,5-substituted aryl pyrroles as glucagon antagonists. WO 98/24780, WO 98/24782, WO 99/24404 and WO 99/32448 (Amgen Inc.) disclose substituted pyrimidinone and pyridone compounds and substituted pyrimidine compounds, respectively, which are stated to possess glucagon antagonistic activity. Madsen et al. (J. Med. Chem. 1998 (41) 5151-7) discloses a series of 2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethanones as competitive human glucagon receptor antagonists. WO 99/01423 and WO 00/39088 (Novo Nordisk A/S) disclose different series of alkylidene hydrazides as glucagon antagonists/inverse agonists.
These known glucagon antagonists differ structurally from the present compounds.
The following is a detailed definition of the terms used to describe the compounds of the invention:
xe2x80x9cHalogenxe2x80x9d designates an atom selected from the group consisting of F, Cl, Br and I.
The term xe2x80x9cC1-6-alkylxe2x80x9d as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like.
The term xe2x80x9cC2-6-alkenylxe2x80x9d as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.
The term xe2x80x9cC2-6-alkynylxe2x80x9d as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
The term xe2x80x9cC1-6-alkoxyxe2x80x9d as used herein refers to the radical xe2x80x94Oxe2x80x94C1-6-alkyl, wherein C1-6-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term xe2x80x9cC1-6-alkanoylxe2x80x9d as used herein denotes a group xe2x80x94C(O)H or xe2x80x94C(O)xe2x80x94C1-5-alkyl. Representative examples are formyl, acetyl, propionyl, butyryl, valeyl, hexanoyl and the like.
The term xe2x80x9cC3-8-cycloalkylxe2x80x9d as used herein represents a saturated, carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term xe2x80x9cC4-8-cycloalkenylxe2x80x9d as used herein represents a non-aromatic, carbocyclic group having from 4 to 8 carbon atoms containing one or two double bonds. Representative examples are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1,4-cyclooctadienyl and the like.
The term xe2x80x9cheterocyclylxe2x80x9d as used herein represents a non-aromatic 3 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or two double bonds. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
The term xe2x80x9carylxe2x80x9d as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.
The term xe2x80x9carylenexe2x80x9d as used herein is intended to include divalent carbocyclic aromatic ring systems such as phenylene, biphenylylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, pentalenylene, azulenylene and the like. Arylene is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthylene, 1,4-dihydronaphthylene and the like.
The term xe2x80x9caryloxyxe2x80x9d as used herein denotes a group xe2x80x94O-aryl, wherein aryl is as defined above.
The term xe2x80x9caroylxe2x80x9d as used herein denotes a group xe2x80x94C(O)-aryl, wherein aryl is as defined above.
The term xe2x80x9cheteroarylxe2x80x9d as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
xe2x80x9cAryl-C1-6-alkylxe2x80x9d, xe2x80x9cheteroaryl-C1-6-alkylxe2x80x9d, xe2x80x9caryl-C2-6-alkenylxe2x80x9d etc. mean C1-6-alkyl or C2-6-alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example: 
The term xe2x80x9coptionally substitutedxe2x80x9d as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
Furthermore, when using the terms xe2x80x9cindependently arexe2x80x9d and xe2x80x9cindependently selected fromxe2x80x9d it should be understood that the groups in question may be the same or different.
The present invention is based on the unexpected observation that the compounds of the general formula (I) disclosed below antagonize the action of glucagon.
The compounds are advantageous by being selective towards the glucagon receptor and show a higher binding affinity for the glucagon receptor compared to the binding affinity for the structurally related GIP (Gastric Inhibitory Peptide) receptor and GIP-1 receptor.
Accordingly, the present inventions relate to compounds of the general formula (I): 
wherein
R1, R2, R3, R4 and R5 independently are hydrogen or C1-6-alkyl,
A is xe2x80x94C(O)xe2x80x94, xe2x80x94CH(OR6)xe2x80x94 or xe2x80x94CHFxe2x80x94,
wherein R8 is hydrogen or C1-6-alkyl,
Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur,
which may optionally be substituted with one or two groups R7 and R8 selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR9, xe2x80x94NR9R10 and C1-6-alkyl,
wherein R9 and R10 independently are hydrogen or C1-6-alkyl,
X is 
wherein
r is 0 or 1,
q and s independently are 0, 1, 2 or 3,
R11, R12, R13 and R14 independently are hydrogen, C1-6-alkyl or C3-8-cycloalkyl,
D is 
wherein
R15, R16, R17 and R18 independently are
hydrogen, halogen, xe2x80x94CN, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CF3, xe2x80x94OCF2CHF2, xe2x80x94S(O)2CF3, xe2x80x94SCF3, xe2x80x94NO2, xe2x80x94OR21, xe2x80x94NR21R22, xe2x80x94SR21, xe2x80x94N R21S(O)2R22, xe2x80x94S(O)2NR21R22, xe2x80x94S(O)NR21R22, xe2x80x94S(O)R21, xe2x80x94S(O)2R21, xe2x80x94C(O)NR21R22, xe2x80x94OC(O)NR21R22, xe2x80x94NR21C(O)R22 xe2x80x94CH2C(O)NR21R22, xe2x80x94OCH2C(O)NR21R22, xe2x80x94C(O)R21, xe2x80x94C(O)R21 or xe2x80x94C(O)OR21,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR21, xe2x80x94NR21R22 and C1-6-alkyl
C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxy, C38-cycloalkyloxy, C38-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C48-cycloalkenyl-C1-6-alkyl,
C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C26-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more sub-stituents selected from halogen, xe2x80x94C(O)OR21, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR21, xe2x80x94NR21R22 and C1-6-alkyl,
wherein R21 and R22 independently are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl,
or R21 and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge xe2x80x94(CR23R24)axe2x80x94O(CR25R26)cxe2x80x94Oxe2x80x94,
wherein
a is 0, 1 or 2,
c is 1 or 2,
R23, R24, R25 and R26 independently are hydrogen, C1-6-alkyl or fluorine,
R19 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C3-8-cyclo-alkyl-C1-6-alkyl,
E is 
wherein
R27 and R28 independently are
hydrogen, halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR32, xe2x80x94NR32R33, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl or aryl,
wherein the aryl group optionally may be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94OR32, xe2x80x94NR32R33 and C1-6-alkyl,
wherein R32 and R33 independently are hydrogen or C1-6-alkyl, or
R32 and R33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
R29, R30 and R31 independently are
hydrogen, halogen, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CF3, xe2x80x94OCF2CHF2, xe2x80x94SCF3, xe2x80x94OR34 xe2x80x94NR34R35xe2x80x94SR34xe2x80x94S(O)R34,xe2x80x94S(C)2R34R35,xe2x80x94OC(O)NR34R35, xe2x80x94NR34C(O)R35, xe2x80x94OCH2C(O)NR34R35, xe2x80x94C(O)R34 or xe2x80x94C(O)OR34,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo-alkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cyclo-alkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, hetero-aryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl,
or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical xe2x80x94Oxe2x80x94(CH2)txe2x80x94CR36R37xe2x80x94(CH2)Ixe2x80x94Oxe2x80x94, xe2x80x94(CH2)txe2x80x94CR36R37xe2x80x94(CH2)Ixe2x80x94 or xe2x80x94Sxe2x80x94(CH2)txe2x80x94CR36R37xe2x80x94(CH2)Ixe2x80x94Sxe2x80x94,
wherein
t and I independently are 0, 1, 2, 3, 4 or 5,
R36 and R37 independently are hydrogen or C1-6-alkyl,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is concerned with compounds of the general formula (Ixe2x80x2) 
wherein
R1, R2, R3, R4 and R5 independently are hydrogen or C1-6-alkyl,
A is xe2x80x94C(O)xe2x80x94, xe2x80x94CH(OR6)xe2x80x94 or xe2x80x94CHFxe2x80x94,
wherein R6 is hydrogen or C1-6-alkyl,
Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur,
which may optionally be substituted with one or two groups R7 and R8 selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR9, xe2x80x94NR9R10 and C1-6-alkyl,
wherein R9 and R10 independently are hydrogen or C1-6-alkyl,
X is 
wherein
r is 0 or 1,
q and s independently are 0, 1, 2 or 3,
R11, R12, R13 and R14 independently are hydrogen, C1-6-alkyl or C3-8-cycloalkyl,
D is 
wherein
R15, R16, R17 and R18 independently are
hydrogen, halogen, xe2x80x94CN, xe2x80x94CH2CN, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CF3, xe2x80x94OCF2CHF2, xe2x80x94S(O)2CF3, xe2x80x94SCF3, xe2x80x94NO2, xe2x80x94OR21 xe2x80x94NR21R22,xe2x80x94SR2, NR21S(O)2 R22 xe2x80x94S(O)2NR21R22, xe2x80x94S(O)NR21R22, xe2x80x94S(O)R21, xe2x80x94S(O)2R21, xe2x80x94C(O)NR21R22, xe2x80x94OC(O)NR21R22, xe2x80x94NR21C(O)R22 xe2x80x94CH2C(O)NR21 R22, xe2x80x94OCH2C(O)NR21R22, xe2x80x94CH2OR21, xe2x80x94CH2NR R2, xe2x80x94OC(O)R2,xe2x80x94C(O)R21 or xe2x80x94C(O)OR21,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR21, xe2x80x94NR21R22 and C1-6-alkyl,
C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8cycloalkyl-C1-6-alkyl, C3-8-cyclo-alkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio,
C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, xe2x80x94C(O)OR21, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR21, xe2x80x94NR21R22 and C1-6-alkyl,
wherein R21 and R22 independently are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl,
or R21 and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge xe2x80x94(CR23R24)axe2x80x94(CR25R26)cxe2x80x94Oxe2x80x94,
wherein
a is 0, 1 or 2,
c is 1 or 2,
R23, R24, R25 and R26 independently are hydrogen, C1-6-alkyl or fluorine,
R19 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl,
E is 
wherein
R27 and R28 independently are
hydrogen, halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR32, xe2x80x94NR32R33, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl or aryl,
wherein the aryl group optionally may be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94NO2 R32 xe2x80x94NR32R33 and C1-6-alkyl
wherein R32 and R33 independently are hydrogen or C1-6-alkyl, or
R32 and R33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
R29, R30 and R31 independently are
hydrogen, halogen, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CF3, xe2x80x94OCF2CHF2, xe2x80x94SCF3, xe2x80x94OR34, xe2x80x94NR34R35, xe2x80x94SR34, xe2x80x94S(O)R34, xe2x80x94S(O)2R34, xe2x80x94C(O)NR34R35, xe2x80x94OC(O)NR34R35, xe2x80x94NR34C(O)R35, xe2x80x94OCH2C(O)N R34R35, xe2x80x94C(O)R34 or xe2x80x94C(O)OR34,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, hetero-aryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl,
or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical xe2x80x94Oxe2x80x94(CH2)txe2x80x94CR36R37xe2x80x94(CH2)Ixe2x80x94Oxe2x80x94, xe2x80x94(CH2)txe2x80x94CR36R37-(CH2)Ixe2x80x94 or xe2x80x94Sxe2x80x94(CH2)txe2x80x94CR36R37xe2x80x94(CH2)Ixe2x80x94Sxe2x80x94,
wherein
t and I independently are 0, 1, 2, 3, 4 or 5,
R36 and R37 independently are hydrogen or C1-6-alkyl,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is concerned with compounds of the general formula (Ixe2x80x3): 
wherein
R1, R2, R3, R4 and R5 independently are hydrogen or C1-6-alkyl,
A is xe2x80x94C(O)xe2x80x94, xe2x80x94CH(O6) or xe2x80x94CHFxe2x80x94,
wherein R is hydrogen, C1-6-alkyl or halogen,
Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur,
which may optionally be substituted with one or two groups R7 and Rxe2x80x9d selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR9, xe2x80x94NR9R10 and C1-6-alkyl,
wherein R9 and R10 independently are hydrogen or C1-6-alkyl ,
X is 
wherein
r is 0 or 1,
q and s independently are 0, 1, 2 or 3,
R11, R12, R13 and R14 independently are hydrogen or C1-6-alkyl,
D is 
wherein
R15, R16, R17 and R18 independently are
hydrogen, halogen, xe2x80x94CN, xe2x80x94CH2CN, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CF3, xe2x80x94OCF2CHF2, xe2x80x94OS(O)2CF3, xe2x80x94SCF3, xe2x80x94NO2, xe2x80x94OR2, xe2x80x94NR21R22, xe2x80x94SR21, xe2x80x94NR21 S(Q)2R22 xe2x80x94S(O)2NR21R22, xe2x80x94S(O)NR2R22, xe2x80x94S(O)R21, xe2x80x94S(OS(O)2R21, xe2x80x94C(O)NR21R22, xe2x80x94OC(O)NR21R22, xe2x80x94NR21C(O)R22, xe2x80x94CH2C(O)NR21R22, xe2x80x94OCH2C(O)NR21R22, xe2x80x94CH2OR21, xe2x80x94CH2R2NR21R22, xe2x80x94OC(O)R21, xe2x80x94C(O)R21 or xe2x80x94C(O)OR,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR21, xe2x80x94NR21R22 and C1-6-alkyl,
C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR21, xe2x80x94NR21R22 and C1-6-alkyl,
wherein R21 and R22 independently are hydrogen, C1-6-alkyl or aryl,
or R21 and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
or two of the groups R15 to R18 when placed in adjacent positions together may form a bridge xe2x80x94(CR23R24)axe2x80x94Oxe2x80x94(CR25R26)cxe2x80x94Oxe2x80x94,
wherein
a is 0, 1 or 2,
c is 1 or 2,
R23, R24, R25 and R26 independently are hydrogen, C1-6-alkyl or fluorine,
R19 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl,
E is 
wherein
R27 and R28 independently are
hydrogen, halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR32, xe2x80x94NR32R33, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl or aryl,
wherein the aryl group optionally may be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94OR32, xe2x80x94NR32R33 and C1-6-alkyl,
wherein R32 and R33 independently are hydrogen or C1-6-alkyl, or
R32 and R33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
R29, R30 and R31 independently are
hydrogen, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CF3, xe2x80x94OCF2CHF2, xe2x80x94SCF3, xe2x80x94OR34, xe2x80x94NR34R35, xe2x80x94SR34, xe2x80x94S(O)R34, xe2x80x94S(O)2R34, xe2x80x94C(O)NR34R35, xe2x80x94OC(O)NR34R35, xe2x80x94NR34C(O)R35, xe2x80x94OCH2C(O)NR34R35, xe2x80x94C(O)R34 or xe2x80x94C(O)OR34,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl,
of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,
or two of the groups R29, R30 and R31 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical xe2x80x94Oxe2x80x94(CH2)txe2x80x94CR36R37xe2x80x94(CH2)Ixe2x80x94Oxe2x80x94, xe2x80x94(CH2)txe2x80x94CR36R37xe2x80x94(CH2)Ixe2x80x94 or xe2x80x94Sxe2x80x94(CH2)txe2x80x94CR36R37xe2x80x94(CH2)Ixe2x80x94Sxe2x80x94,
wherein
t and I independently are 0, 1, 2, 3, 4 or 5,
R36 and R37 independently are hydrogen or C1-6-alkyl,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
In one embodiment, R1, R2, R3, R4 and R5 are hydrogen.
In one embodiment, A is xe2x80x94CHFxe2x80x94.
In another embodiment, A is xe2x80x94CH(OR6)xe2x80x94, wherein R6 is as defined for formula (I), such as xe2x80x94CH(OH)xe2x80x94.
In one embodiment, Z is 
wherein R7 and R8 are as defined for formula (I), such as 
In one embodiment, X is 
wherein q is 0 or 1, r is 0 or 1, s is 0, 1 or 2, and R12 and R13 independently are hydrogen or C1-6-alkyl.
In another embodiment, X is xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NHCH2xe2x80x94, xe2x80x94C(O)NHCH(CH3)xe2x80x94, xe2x80x94C(O)NHC(CH3)2xe2x80x94, xe2x80x94C(O)NHCH2CH2xe2x80x94, xe2x80x94C(O)CH2xe2x80x94, xe2x80x94C(O)CH2CH2xe2x80x94, xe2x80x94C(O)CHxe2x95x90CHxe2x80x94, xe2x80x94(CH2)sxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94NHC(O)xe2x80x94, wherein s is 0 or 1.
In yet another embodiment, X is xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NHCH2xe2x80x94, xe2x80x94C(O)NHCH(CH3)xe2x80x94, xe2x80x94C(O)NHCH2CH2xe2x80x94, xe2x80x94C(O)CH2xe2x80x94, xe2x80x94C(O)CHxe2x95x90CHxe2x80x94, xe2x80x94(CH2)sxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94or xe2x80x94NHC(O)xe2x80x94, wherein s is 0 or 1.
In still another embodiment, X is xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NHCH2xe2x80x94, xe2x80x94C(O)NHCH(CH3)xe2x80x94, xe2x80x94C(O)NHCH2CH2xe2x80x94, xe2x80x94C(O)CH2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94NHC(O)xe2x80x94. In still a further embodiment, X is xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NHCH2xe2x80x94, xe2x80x94C(O)NHCH(CH3)xe2x80x94, xe2x80x94C(O)CH2xe2x80x94 or xe2x80x94C(O)xe2x80x94, such as xe2x80x94C(O)NHxe2x80x94.
In one embodiment, D is 
wherein R15, R16, R17, R18, R19 and R20 are as defined for formula (I).
In another embodiment, D is 
wherein R15, R16 and R17 are as defined for formula (I).
In one embodiment, R15, R13 and R17 are independently hydrogen, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94SCF3, C1-6-alkyl, C1-6-alkoxy, xe2x80x94S-C1-6-alkyl, xe2x80x94C(O)OR21, xe2x80x94C(O)R21, xe2x80x94CH2OR21, xe2x80x94C(O)NR21R22, xe2x80x94S(O)R21, xe2x80x94S(O)2R2, xe2x80x94S(O)2CF3, xe2x80x94S(O)2NR21R22, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkoxy or C3-8-cycloalkyl-C1-6-thioalkyl, or
aryl, heteroaryl or aryloxy, which may optionally be substituted with xe2x80x94CF3, xe2x80x94OCF3, C1-6-alkyl, halogen or xe2x80x94C(O)OR21, or
two of the groups R15, R16 and R17 when placed in adjacent positions together form a bridge xe2x80x94(CR23R24)axe2x80x94Oxe2x80x94(CR25R26),xe2x80x94Oxe2x80x94,
wherein R21 and R22 independently are hydrogen or C1-6-alkyl, and a, c, R23, R24, R25 and R26 are as defined for formula (I).
In another embodiment, R15, R16 and R17 are independently hydrogen, halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3 or C1-6alkoxy or wherein R15 and R16 together form a bridge xe2x80x94CF2xe2x80x94Oxe2x80x94CF2xe2x80x94Oxe2x80x94 and R17 is hydrogen.
In yet another embodiment, R15, R16 and R17 independently are hydrogen, halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3 or C1-6-alkoxy.
In another embodiment, D is 
wherein R15, R16, R19 and R20 are as defined for formula (I).
In yet another embodiment, D is 
wherein R15 and R16 are both hydrogen and R19 is C1-6-alkyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl.
In still another embodiment, D is 
wherein R15 and R16 are both hydrogen and R19 and R20 are both C1-6-alkyl.
In one embodiment, E is 
wherein R27 R28 R29 R30 and R31 are as defined for formula (I).
In another embodiment, E is 
wherein R27 and R28 are as defined for formula (I).
In still another embodiment, E is 
wherein R27 and R28 are as defined for formula (I).
In one embodiment, R27 and R28 are independently hydrogen, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl or phenyl, wherein the phenyl group is optionally substituted as defined for formula (I).
In another embodiment, R27 and R2-3 are independently hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl.
In still another embodiment, R27 is hydrogen and R28 is C1-6-alkyl or C3-8-cycloalkyl, such as tert-butyl, cyclohexyl or cyclohexenyl.
In another embodiment, E is 
wherein R29, R30 and R31 are as defined for formula (I).
In yet another embodiment, E is 
wherein R29, R30 and R31 are as defined for formula (I).
In one embodiment, R29, R30 and R31 are independently
hydrogen, xe2x80x94CHF2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2CF3, xe2x80x94OCF2CHF2, xe2x80x94SCF3, xe2x80x94OR34, xe2x80x94NR34R35, xe2x80x94SR34, xe2x80x94S(O)R34, xe2x80x94S(O)2R34, xe2x80x94C(O)NR34R35, xe2x80x94OC(O)NR34R35, xe2x80x94NR34C(O)R35, xe2x80x94OCH2C(O)NR34R35, xe2x80x94C(O)R34 or xe2x80x94C(O)OR34,
C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl
C3-8-cycloalkyl or C4-8-cycloalkenyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
In yet another embodiment, R29, R30 and R31 are independently
hydrogen, C1-6-alkoxy, halogen, xe2x80x94CF3, OCF3 or xe2x80x94NR34R35, wherein R34 and R35 are as defined for formula (I), or
C1-6-alkyl, C3-8cycloalkyl or C4-8-cycloalkenyl, which are optionally substituted as defined for formula (I).
In still another embodiment, R29 R30 and R3 are independently
hydrogen or
C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl, which are optionally substituted as defined for formula (I).
In yet another embodiment, R29, R30 and R31 are independently
hydrogen or
C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl,
or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
In another embodiment, R29 and R31 are both hydrogen, and R30 is different from hydrogen.
In still another embodiment, R29 and R31 are both hydrogen, and R30 is C3-8-cycloalkyl or C4-8-cycloalkenyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl,
or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
In yet a further embodiment, R29 and R31 are both hydrogen, and R30 is C4-8-cycloalkenyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl,
or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
In still a further embodiment R29 and R31 are both hydrogen, and R30 is cyclohexenyl,
which may optionally be substituted with one or more substituents selected from halogen, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94NO2, xe2x80x94OR34, xe2x80x94NR34R35 and C1-6-alkyl,
wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl,
or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
In another embodiment, R30 is substituted with one C1-6-alkyl substituent, such as tert-butyl or methyl.
In still another embodiment, R29, R30 and R31 are independently hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl.
In yet another embodiment, R29 and R31 are both hydrogen and R30 is C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl, such as tert-butyl, cyclohexyl or cyclohexenyl.
In one embodiment, the invention relates to a compound of the general formula (I1): 
wherein R1, R2, R3, R4, R5, R6, R7, R8, X, D and E are as defined for formula (I) or in any one of the preceding embodiments.
In one embodiment, the invention relates to a compound of the general formula (I2): 
wherein R1, R2, R3, R4, R5, R6, R7, R8, D and E are as defined for formula (I) or in any one of the preceding embodiments.
In one embodiment, the invention relates to a compound of the general formula (I3): 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R15, R16, R17, R29, R30, and R31 are as defined for formula (I) or in any one of the preceding embodiments.
In one embodiment of the formulae (I1), (I2) and (I3), R1, R2, R3, R4, R5, R6, R7 and R8 are hydrogen.
In one embodiment, the invention relates to a compound of the general formula (I4): 
wherein R1, R2, R3, R4, R5, R7, R8, X, D and E are as defined for formula (I) or in any one of the preceding embodiments.
In one embodiment, the invention relates to a compound of the general formula (I5): 
wherein R1, R2, R3, R4, R5, R7, R8, D and E are as defined for formula (I) or in any one of the preceding embodiments.
In one embodiment of the formulae (I4) and (I5), R1, R2, R3, R4, R5, R7 and R8 are hydrogen.
The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the invention.
Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.
The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane-sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the like.
Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds, are able to form.
Furthermore, the pharmaceutically acceptable salts comprise basic amino acid salts such as lysine, arginine and ornithine.
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of the compounds of the general formula (I), which are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
The invention also encompasses active metabolites of the present compounds.
The compounds according to the present invention act to antagonize the action of glucagon and are accordingly useful for the treatment and/or prevention of disorders and diseases in which such an antagonism is beneficial.
Accordingly, the present compounds may be applicable for the treatment and/or prevention of hyperglycemia, IGT (impaired glucose tolerance), insulin resistance syndromes, syndrome X, Type 1 diabetes, Type 2 diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, etc.
Furthermore, they may be applicable as diagnostic agents for identifying patients having a defect in the glucagon receptor, as a therapy to increase gastric acid secretions and to reverse intestinal hypomobility due to glucagon administration.
Accordingly, in a further aspect the invention relates to a compound according to the invention for use as a medicament.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients.
The pharmaceutical composition is preferably in unit dosage form comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to the invention.
Furthermore, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of a disorder or disease, wherein a glucagon antagonistic action is beneficial.
The invention also relates to a method for the treatment and/or prevention of disorders or diseases, wherein a glucagon antagonistic action is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment and/or prevention of any glucagon-mediated conditions and diseases.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment and/or prevention of hyperglycemia.
In yet a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.
In another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.
In still another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.
In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.
In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 1 diabetes. Such treatment and/or prevention is normally accompanied by insulin therapy.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of obesity.
In yet a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of disorders of the lipid metabolism, such as dyslipidemia.
In still a further embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of an appetite regulation or energy expenditure disorder.
In a further aspect of the invention the present compounds are combined with diet and/or exercise.
In yet a further aspect of the invention the present compounds are administered in combination with one or more further active substances in any suitable ratios. Such further active agents may be selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes.
Suitable antidiabetic agents comprise insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), eg Nxcex5B29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), eg AspB28 human insulin, U.S. Pat. No. 5,504,188 (Eli Lilly), eg LyB28Pro B29 human insulin, EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise imidazolines, sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, agents acting on the ATP-dependent potassium channel of the 3-cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00137474 (Novo Nordisk A/S) which are incorporated herein by reference, or nateglinide or potassium channel blockers such as BTS-67582, insulin sensitizers, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.
In one embodiment of the invention the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as NB29-tetradecanoyl des (B30) human insulin, AspB28 human insulin, LysB28 ProB29 human insulin, Lantus, or a mix-preparation comprising one or more of these.
In a further embodiment of the invention the present compounds are administered in combination with a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide or glicazide.
In another embodiment of the invention the present compounds are administered in combination with a biguanide eg metformin.
In yet another embodiment of the invention the present compounds are administered in combination with a meglitinide eg repaglinide or nateglinide.
In still another embodiment of the invention the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011/Cl-1037 or T174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy""s Research Foundation).
In still another embodiment of the invention the present compounds may be administered in combination with an insulin sensitizer such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy""s Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S).
In a further embodiment of the invention the present compounds are administered in combination with an xcex1-glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.
In another embodiment of the invention the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the xcex2-cells eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glicazide, BTS-67582, repaglinide or nateglinide.
In still another embodiment of the invention the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
In another aspect of the invention, the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with metformin and a sulphonylurea such as glibenclamide or glyburide; a sulphonylurea and acarbose; metformin and a meglitinide such as repaglinide; acarbose and metformin; a sulfonylurea, metformin and troglitazone; a sulfonylurea, metformin and pioglitazone; a sulfonylurea, metformin and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; a meglitinide such as repaglinide, metformin and troglitazone; a meglitinide such as repaglinide, metformin and pioglitazone; a meglitinide such as repaglinide, metformin and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; insulin and a sulfonylurea; insulin and a meglitinide such as repaglinide; insulin and metformin; insulin, metformin and a meglitinide such as repaglinide; insulin, metformin and a sulfonylurea; insulin and troglitazone; insulin and pioglitazone; insulin and an insulin sensitizer such as such as disclosed in WO 00/63189 or WO 97/41097; insulin and lovastatin; an insulin analogue or derivative, metformin and a meglitinide such as repaglinide; an insulin analogue or derivative, metformin and a sulfonylurea; an insulin analogue or derivative and troglitazone; an insulin analogue or derivative and pioglitazone; an insulin analogue or derivative and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; an insulin analogue or derivative and lovastatin; etc.
Furthermore, the compounds according to the invention may be administered in combination with one or more antiobesity agents or appetite regulating agents.
Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide xcex3) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) modulators, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, xcex23 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or citalopram, serotonin and noradrenaline reuptake inhibitors, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA (dopamine) agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR xcex2 agonists.
In one embodiment of the invention the antiobesity agent is leptin.
In another embodiment of the invention the antiobesity agent is dexamphetamine or amphetamine.
In another embodiment of the invention the antiobesity agent is fenfluramine or dexfenfluramine.
In still another embodiment of the invention the antiobesity agent is sibutramine.
In a further embodiment of the invention the antiobesity agent is orlistat.
In another embodiment of the invention the antiobesity agent is mazindol or phentermine.
Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are xcex2-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and cc-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
It should be understood that any suitable combination of the compounds according to the invention with diet and/or exercise, one or more of the above-mentioned compounds and optionally one or more other active substances are considered to be within the scope of the present invention.
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is a base addition salt of a compound having the utility of a free acid. When a compound of the formula (I) contains a free acid such salts are prepared in a conventional manner by treating a solution or suspension of a free acid of the formula (I) with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above.
For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho-lipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet that may be prepared by conventional tabletting techniques may contain:
If desired, the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.